This prospective study investigated the value of serum total prostate specific antigen (tPSA)-based parameters in the diagnosis of prostate cancer (PCa). Serum tPSA, free to tPSA ratio (f/tPSA), PSA density (PSAD), and PSA transition zone (PSAT) were evaluated in 110 patients with histologically confirmed benign prostate hyperplasia (BPH) and 98 patients with PCa. Once the serum tPSA was elevated (greater than 4 ng/ml) or digital rectal examination (DRE) was suspicious, transrectal ultrasound-guided biopsies were recommended. The tPSA, f/tPSA, PSAD, and PSAT levels were significantly different between the BPH and PCa groups. In patients with a tPSA level of 4.1-9.9 ng/ml or an abnormal DRE finding, only PSAT was found to have discriminating power. The cut-off values were 0.15 for f/tPSA, 0.30 for PSAT, and 0.15 for PSAD. The diagnostic sensitivity of a positive result for one of these parameters in the whole group was 84%, but 75% in patients with a tPSA of 4.1-9.9 ng/ml or an abnormal DRE finding. The diagnostic specificity of positive results for 3 parameters was 92% in the whole group and 93% in patients with a tPSA of 4.1-9.9 ng/ml or an abnormal DRE finding. All parameters were influenced by the histological grades. Histological grades showed a negative correlation (r = -0.56) with f/t PSA and a positive correlation (r = 0.44) with PSAT. No diagnostic marker investigated heretofore was able to rule out or detect early PCa in patients with a PSA level of 4.1-9.9 ng/ml. Using the PSA-based parameters together can be helpful in management of these patients. If all of the PSA-based parameters are negative, biopsy might be postponed; patients who have three positive PSA-based parameters should be biopsied. In case of one or two of the parameters, the patient's age and race should be considered in clinical decision-making.